preparation of 1-azacyclododeca-3,8-diynes and 1,6-diazacyclododeca-3,8-diynes

FULL PAPER

Preparation of l-Azacyclododeca-3,8-diynes and 1,6-Diazacyclododeca-3,8-diynes Joachim Ritter and Rolf Gleiter*

Organisch-Chemisches Institut der Universitat Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany

Received May 26, 1997

Keywords: Medium-sized rings I Cyclizations I Alkynes I Heterocycles I Multicomponent reactions

The preparation of N, N‘-dialkyl- and N, N‘-diaryl- 1,6-diazacyclodeca-3,8-diynes was achieved by reaction of alkyl- or arylamines with 1,4-dihalobut-2-yne under dilution conditions in yields of 5- 15%. The compounds synthesized by this procedure were the N,N’-dimethyl (2b), N,N’-diethyl (2c), N, N’ -diisopropyl (2d), N, N’ -di- tert-butyl (2e), N, N’ -dicyclohexyl (2f), N,N’-diphenyl (2g), and N,N’-di-p-tolyl (2h) derivatives. The parent compound 2a was obtained in ca. 40% yield by heating 2d with a-chloroethylchloroformate (20).

Using 1,9-dibromonona-2,?-diyne (10) and methylamine or isopropylamine, respectively, the corresponding N-alkyl- 1- azacyclodeca-3,8-diynes 4b and 4d were synthesized under dilution conditions. By heating 4d with 20 we obtained 1- azacyclodeca-3,8-diyne (4a). As side products of the cyclization reactions the trimers 18 and tetramers 12 and 19 were isolated and characterized. N-methyl-1-azacycloundeca-3,9- diyne (14b) was prepared by reaction of 1,lO-dibromodeca- 3,8-diyne (13) with methylamine.

Recently, we and others have shown that cyclic alkynes and dialkynes show unique reactivity and reveal interesting electronic properties[’]. Examples for corresponding nitro- gen-containing cycloalkynes, especially with the amine functionality in the propargylic position, are rare and no common synthetic route has been published[’]. We expect this class of compounds to provide new insight into amine- alkyne interactions. For example, insertion of one triple bond each between the C-C bonds of piperazine (1) leads to 1,6-diazacyclodeca-3,8-diyne (2a). The transformation of the six-membered ring of 1 into the ten-membered ring of 2 implies several consequences: The torsional strain between the CH2 groups as well as the 1,3-interactions in 1 are reduced Because of these reduced interactions, 2 and its alkyl- and aryl-substituted derivatives are interesting model compounds for conformational stud- i e ~ [ ~ l [ ~ ] . The same holds for 1 -azacyclodeca-3,8-diyne (4a) and its substitution products which are related to piperidine (3). In previous communications we have shown that diazacyclodecadiynes show interesting reactivity[s1[6] and can serve as new building blocks for novel macrocyclic caged’]. In this paper we report the preparation of 2a, its N,N’-dimethyl (b), N,N’-diethyl (c), N,N’-diisopropyl (d), N,N‘-di- tert-butyl (e), N,N’-dicyclohexyl (0, N,N-diphenyl (g) and N,N’-di-p-tolyl (h) derivatives, and 4a and its N-methyl and N-isopropyl derivatives.

Results The synthesis of strained cycloalkynes requires methods

compatible with the enhanced reactivity of the bent triple bond. From a retrosynthetic perspective a disconnection of the propargylic C-N bonds of 2 and 4 appeared to provide the most appropriate synthetic approach to these diynes. Accordingly, nucleophilic halide replacement in the propar-

- - R-N N-R R-N N-R

\ / \ /

f - 7 - - U

1 2

3 4

gylic position with amines, known to proceed under relatively mild conditions, was chosen to perform the ring clo- sure. From all possible synthon combinations we decided to use those with separated halide and amine functions as synthetic precursors. This is due to the fact that molecules containing amine and propargylic halide functionalities are highly labile with respect to quaternization. We found that azacyclization of propargylic dihalides with primary amines provides a common route to cyclic azaalkynes such as 2, 4 and their homologs.

A. Synthesis of N-Alkylazacyclodeca-3,8-diynes

The synthesis of 4b and 4d could be achieved by azacyclization of 1,9-dibromonona-2,7-diyne (10). In Scheme 1 two routes to prepare 10 from dibromopropane (5) are out- lined.

Reaction of 5 with the ethylendiamine complex of the monolithium salt of acetylene (6)181 in DMSO yielded 1,6- heptadiyne (8). The preparation of nona-2,7-diyne- 1 ,O-diol

Liebigs Ann./Recueill997,2113-2118 0 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1997 0947-3440/97/1010-2113 $17.50+.50/0 21 13

FULL PAPER J. Ritter, R. Gleiter

Scheme 1

Br n Br Br n Br

5 5

+ L l C r C H . EDA + LIC-CCHZ-OTHP

6 7

1.

I I HOH,C CHzOH

9

Br Br

10

a) DMSO, 25°C. - b) n-Butyllithiumlhexanelether, -20°C. - c) Paraformaldehyde/THF, -10 to 40°C - d) H20. - e) DMPU/ THF, 0-25°C. - f) 15% HCUEtOH, 80°C. - g) PBr,/Et,O/pyri- dine.

(9)[s1[91[101[' l] was achieved from 8 by reaction of its dilith- ium salt - prepared in situ from 8 and n-butyllithium - and paraformaldehyde. A second path which led to 9 was the reaction of 5 with the lithium salt of 2-propargyloxyte- trahydropyran (7) and subsequent hydrolysis of the protecting groups. Both pathways gave, however, similar overall

Scheme 2. R = CH3 (b), i-C3H7 (d)

a + R-NHz -

Br

10 11

<Tr + CH,-NH,

13 Br l l b

yields. The bromination of 9 with PBr3 in presence of pyri- dine in ether provided The cyclization of 10 with methylamine or isopropylamine has been achieved by a two-component dilution apparatus in the presence of potassium carbonate as base (Scheme 2). The yield of the cyclization reaction was 10- 14%.

The 20-membered tetrayne side products 12 were isolated in 6-100/0 yield. Compounds 4b and 12b have been prepared before by a ten-step procedure (overall yield Similarly, the preparation of N-methyl-1 -azacycloundeca- 3,9-diyne (14b) had been achieved from the dibromide 13.

B. Syntheses of N-Substituted 1,6-Diazacyclodeca-3,8-diynes

The syntheses of N,N'-dialkyl- and N,N1-diaryl-l,6-diazacyclodecadiynes (2b-2h) have been achieved by a four- and a two-component reaction by adding simultaneously the primary amine 11 and 1,4-dibromo-2-butyne (15). To achieve maximum yields we added a 0.4 M solution of the amine and the dibromide synchronously during 8 h to a suspension of K2C03 in THE The isolated yields obtained by this technique were 8 - 15%, with the highest isolated yield being obtained for 2d (12-15%). Addition of the amine to the dibromide, in a one-component dilution reaction reduced the yield by a factor of 2. Alternatively, we prepared 2b from 15 and 1,4-bis(methylamin0)-2-butyne (17) (Scheme 3). The latter compound was obtained from 15 and a 50-fold excess of methylamine (llb). The yield of 2b by this pathway was about the same as in the one-pot reaction described above. Taking into account the purification of 17, this alternative offers no advantage to the one- pot synthesis of 2.

As side products we always obtained the trimers 18 and the tetramers 19. The isolation of the macrocycles has been achieved by chromatography on alumina with cyclohexanel ethylacetate as solvent.

Considering the number of possible reactions in the four- component reaction, the yield for 2d is surprisingly high. Monitoring the reaction by GUMS allowed us to indentify intermediates iPrNHCH2C=CCH2Br (21d), iPrN- (CH2C=CCH2Br)2 (22d), iPrNHCH2C=CCH2NHiPr

4 12

~

/ - \

\ N-CH,

L J 14b

a) K2C03/THF, 40°C.

21 14 Liebigs Ann.lRecuei1 1997, 2113-21 18

l-Azacyclododeca-3,8-diynes and 1,6-Diazacyclododeca-3,8-diynes FULL PAPER Scheme 3. R = CH3 (b), C2H5 (c), i-C3H7 (d), t-C,H, (e), c-C6H,, (0; X = Br (15), p-C7H7S03 (16)

~

~

/ - \ + R-NH, - R-N N-R a / - /

X X - -

~

~

/ - \ + R-NH, - R-N N-R a / - /

X X - -

15.16 11 2

18 1s

(23d), and iPrNHCH2C-CCH2N(iPr)CH2C=CCH2Br (24d). Three intermolecular and one final intramolecular SN reactions are required for each reaction channel leading to the cyclic diyne 2d [e.g. 15 + l l d + 21d ( I ) , 21d + 15 + 22d (2), 22d + l l d + 24d (3), 15 t 24d -+ 2d (4)]. An average yield of more than 60% for each reaction step results in an overall isolated yield of 15%. Warning: Attempts to purify 18 and 19 by Kugelrohr distillation resulted in ex- plosion!

The synthesis of the N,N-diaryl-l,6-diazacyclodeca-3,8- diynes (2g, 2h) could be achieved by using the 1,4-ditosyl- 2-butyne (16) rather than the dibromide 15 and activated K2C03 (13O0C/O.2 Torr). With this modification 2g and 2h could be obtained in 5% yield. We isolated 18g and 18h in 7% yield.

C. Preparation of the Parent Systems 2a and 4a

Both parent systems, 2a and 4a, are secondary amines. We assumed these could be prepared from primary amines in which the substituent R can be removed after the cyclization step; however, removal of the protecting group proved to be problematic. Attempts with protecting groups such as methoxy, tosyl, trifluoroacetyl and trimethylsilyl groups, applying standard deprotection procedures[14], led to de-

composition initiated by transannular reaction of the triple bonds.

We finally succeeded using a procedure suggested by Olofson et al.[15] which is based on work published by Ga- damer et al.[16] and von Bruchhausen et al."']. This procedure has been used successfully for N,N'-dimethylpipera- zine (lb). Treatment of l b with a-chloroethylchloroformate (20) removed both methyl groups. In the case of 2 the opti- mum yield (25-40%) was obtained by heating 2d with 3.2 equivalents of 20 for 2-3 d at 80°C in 1,2-dichloroethane and subsequent hydrolysis. Similar yields were obatined by using 4d as starting material. Both, 2a and 4a were purified by sublimation. The relatively low yield compared with di- methylpiperazine (96%1)[~~] we ascribe to a reaction of the acid chloride with the triple-bond system['s] (Scheme 4).

Conclusion

By using a simple four- or two-component condensation procedure with a primary amine and a,o-dihalide, applying dilution conditions, we were able to synthesize effectively the 1-mono- and 1,6-diazacyclodeca-3,8-diynes 2b-2h as well as 4b and 4d. Although the yields are low ( 5 - 150/0) the starting materials are readily available and thus the aza- and diazacyclodecadiynes could be prepared in multigram quantities within one week of work. In most cases we could isolate the trimers and tetramers as side products. Their chemistry is unknown and is currently under investigation. Removal of the isopropyl groups of 2d and 4d using a highly selective dealkylation reagent provides the parent compounds 2a and 4a. By introducing alkyl groups with better leaving properties it should be possible to increase the yield of the parent secondary amines.

We are grateful to the Deutsche Forschungsgemeinschaft (SFB 247), the Fonds der Chemischen Industrie and the BASF Aktienge- sellschuft, Ludwigshafen, for financial support.

Scheme 4

2b 20 2a

a) Molecular sieves (4 A), (CH2)2C12, 2-3d, 80°C. - b) CH,OH, 50°C. - c) NaOH/H20.

Liehigs Ann.lRecueill997, 2113-2118 2115


Experimental Section Melting points (uncorrected): Dr. Tottoli (Biichi). - IH NMR

(solvent as internal standard): 300 MHz: Bruker WH 300; 200 MHz: Bruker AS200. - I3C NMR (solvent as internal standard): 50.32 MHz: Bruker AS 200, 75.46 MHz: Bruker WH 300. Unless otherwise noted, the 'H-NMR spectra were recorded at 300 MHz in CDC13 and the I3C-NMR spectra at 75.46 MHz in CDC13. - GCIMS: Hewlett Packard HP 59970CD GUMS-MSD Work- station. - High-resolution mass spectra: ZAB, Vakuum Gener- ators. - Elemental Analysis: Mikroanalytisches Laboratorium der Chemischen Institute der Universitlt Heidelberg

Procedures jor the Synthesis of Nonu-2,7-diyne-l,Y-diol (9). - Path The reaction was carried out under argon. To a solution of 17.3g (0.19 mol) of 1,6-heptadiyne (8) in 500 ml of dry ether a solution of 160 ml of n-butyllithium (2.5 M in hexane) was added at -70°C. After completion, 13.35 g (0.45 mol) of paraformaldehyde was added and the mixture was refluxed for 8 h. After cooling, the mixture was solvolyzed by the addition of 150 ml of water. The aqueous layer was extracted several times with ether, the organic phase was dried with MgS04 and concentrated. The raw material (24 g, 80% of 9 ) was used for further reactions.

Path B[loI["]: To a solution of 101.3g (0.72 mol) of 2-propargyl- oxytetrahydropyran in 400 ml of dry THF a solution of 250 ml(0.8 mol) of n-butyllithium (2.5 M in hexane) was added at 5°C to pro- duce the lithium salt 7. The mixture was stirred for 1 h at room temp. and subsequently added under ice-cooling to 66.6 g (0.33 mol) of 1,3-dibromopropane (5) in 800 ml of dry and oxygen-free N,N'-dimethylpropyleneurea (DMPU). Stirring was continued for 12 h at room temp. followed by hydrolysis with 130 ml of methanol and 650 ml of water. The mixture was extracted several times with ether. After washing the ethereal phase with water and drying (Na2S04), the solvent was removed. The residue was solvolyzed with 1.5 1 of ethanol and 130 ml of diluted (15%) HCI under reflux for 12 h. After cooling, the ethanol was removed and the aqueous phase extracted several times with ether. After drying (Na,SO,), the ether was removed. The remaining raw material (17.06 g, 37% of 9)[101["l was used for further reactions.

General Procedure for the Preparation of 4b, 4d, 2b-2h and 14b: The reactions were carried out under argon. To a solution of 2.5 1 of THF (and 9 ml of HzO in the case of aliphatic amines) K2C03 was added with stirring and the mixture refluxed under argon. Both components, the aliphatic amine and the dihalide or ditosylate, were added to the mixture synchronously within 8-10 h. The temperature of the bath was maintained between 50 and 60°C. In the case of methylamine it was kept below 45°C. After the addition had been completed, stirring was continued for 1-2 d. After ter- mination of the reaction, the mixture was filtered and the residue was washed carefully with THE The cyclic amines were extracted from the solvent with 100-200 ml of an aqueous 0.5 M HCl solution saturated with NaCl. To remove residues of THF from the aqueous phase it was extracted with ether.

The free amines were extracted from the aqueous phase by the addition of either 300 ml of ether, CHC13 or CH2C12 and 2 M

NaOH at 0- 10°C until a pH > 11 was obtained. The solution was saturated with NaCl and the aqueous phase was extracted with 200 ml of the solvent. The collected organic phases were dried with K2C03 and concentrated (< 40°C) until about 400 ml of solvent remained. For purification by chromatography 250 ml of A1203 I11 was added and the evaporation was completed. Chromatography was carried out with A1203 I11 by using cyclohexanelethyl acetate for aliphatic and toluenelcyclohexane for aromatic amines. The aliphatic ten-membered rings could be crystallized from ether, cyclo-

2116

hexane and chloroform. The compounds with aromatic substitu- ents crystallized well from toluene or benzene. The 15- and 20- membered rings crystallized very slowly. In the case of aromatic amines no water was added and the K2C03 had to be activated by heating at 13O0C/O.2 Torr for several hours.

N-Methyl-l-azacyclodeca-3,8-diyne (4b) and NN-Dinzethyl-1,l I - diazacycloeicosa-3,8,13,18-tetrayne (12b): Starting materials: Aque- ous (40%) solution of methylamine (7.75 g, 0.1 mol) in 500 ml of THF, 27.8 g (0.1 mol) of 1,9-dibromonona-2,7-diyne (10)[l2] in 500 ml of THF, 42g (0.3 mol) of potassium carbonate, 2.5 1 of THF and 9 ml of water. Column chromatography with AI2O3 111 (cyclohexanelethyl acetate 1O:l) yielded 1.32-1.5 g (9-11%) of 4b and 0.44-0.74 g (3-5%) of 12b as colorless oils. - 4b: 'H NMR: 6 = 3.41 (t, 4 H, 5J = 2.2 Hz), 2.47 (s, 3 H), 2.40-2.27 (tt, 4 H, 5J 2.2 Hz, 3J 1 5.8 Hz), 1.74-1.66 (q, 2 H, 3J = 5.8 Hz). - 13C NMR: 6 = 87.1, 77.9, 46.5, 39.4, 25.7, 19.7. - GUMS (EI); mlz (!A,): 147 (16), 146 (loo), 145 (lo), 144 (23), 131 (42), 118 (37), 91 (47), 77 (33). - 12b: 'H NMR: 6 = 3.37 (t, 8 H, 5J = 2.2 Hz), 2.32 (s, 6 H), 2.40-2.30 (tt, 8 H, 5J = 2.2 Hz, 3J = 7.2 Hz), 1.71-1.66 (q, 4 H, 35 = 7.2 Hz). - I3C NMR 6 = 84.4, 75.9, 44.8,41.4, 27.3, 17.6. - HRMS (C2,,Hz6N2): calcd. 294.2094; found 294.2054.

N-Isopropyl-l-azacyclodeca-3,8-diyne (4d) and N N'-Diisopropyl- I , 1 I-diazacycloeicosa-3,8,13,18-tetruyne (12d): Starting materials: 5.90 g (0.1 mol) of an aqueous solution (40%) of isopropylamine in 500 ml of THF, 27.8 g (0.1 mol) of 1,9-dibromonona-2,7-diyne ( lo) , 42 g (0.3 mol) of K2C03, 2.5 1 of THF and 9 ml of water. Extration with ether. Column chromatography on silica gel (cyclohexanelethyl acetate 5:l) yielded 2.63 g (15%) of 4d and 1.75 g (190/,) of 12d. - 4d: m. p. 58°C - 'H NMR: 6 = 3.55 (s, 4H), 3.37 (sept, 1 H), 2.33 (m, 4 H), 1.73 (m, 2 H), 1.11 (d, 6 H). - 13C NMR: 6 = 87.3, 78.6, 47.1, 43.3, 25.6, 19.9. - GCIMS (EI); mlz ("/o): 176 (l), 175 (9), 161 (12), 160 (loo), 158 (lo), 144 (19), 132

(ll), 77 (17), 65 (ll), 51 (12), 43 (13), 41 (23). - C12H17N (175.3): (21), 130 (12), 128 (25), 118 (13), 117 (29), 115 (16), 91 (41), 79

calcd. C 82.23, H 9.78, N 7.99; found C 82.18, H 9.85, N 7.91. - 12d: IH NMR: 6 = 3.52 (s, 8 H), 2.90 (sept, 2 H), 2.34 (m, 8 H), 1.69 (m, 4 H), 1.08 (d, 12 H). - I3C NMR: 6 = 84.1, 78.0, 50.8, 40.5, 28.9, 20.6. - C24H34N2 (350.6): calcd. C 82.23, H 9.78, N 7.99; found C 81.65, H 9.61, N 8.04.

N-Methyl-l-azacycloundeca-3,8-diyne (14b): Starting materials: 7.75 g (0.1 mol) of an aqueous solution (49%) of methylamine in 500 ml of THF, 29.2 g (0.1 mol) of l,lO-dibromodeca-2,8-diyne (13) in 500 rnl of THF, 42g (0.3 mol) of K2C03, 2.5 1 of THF and 9 ml of water. Extraction with ether. Column chromatography on A1203 111 (cyclohexanelethyl acetate 10: I ) yielded 805 mg (5%) of 14b as a colorless oil. - 'H NMR: 6 = 3.39 (t, 4 H, 5J = 2.2 Hz), 2.42(~,3H),2.10(m,4H),1.73-1.60(m,4H).-'~CNMR:F= 86.8, 78.0, 46.3, 39.6, 28.0, 20.3. - GCIMS (EI); mlz (%): 161 (lo), 160 (58), 144 (19), 133 (41), 132 (loo), 118 (30), 117, (32), 105 (lo), 91 (46), 77 (34), 65 (21), 42 (61).

NN-Dimethyl-l,6-diazacyc~odeca-3,8-diyne (2b), NN',N"-Tri- methyl-], 6, Il-triazacyclopentadeca-3,8,13-triyne (18b), N; N', W, W - Tetrameth~&l,4, I I , 16-tetrauzaeycloeicosa-3,8,13,18-tetrayne (19b): Starting materials: 15.5 g (0.2 mol) of an aqueous solution (40%) of methylamine in 500 ml of THE; 42.4 g (0.2 mol) of 1,4-dibromo- 2-butyne (15) in 500 ml of THF, 69 g ( 0.5 mol) of K2C03, 2.5 1 of THF and 9 ml of water. The cyclization reaction was carried out at 40-45°C. Column chromatography on AI2O3 I11 (cyclohexane/ ethyl acetate 1O:l) yielded 1.33-1.62 g (8-10%)) of 2b, 0.83-1.25g (5-7%1) of 18b and 0.5-0.75 g (4-60/0) of 19b. - 2b: Colorless crystals from ether, m. p. 121 "C. - 'H NMR (200 MHz, CDCl3): F = 3.49 (s, 8 H), 2.52 (s, 6 H). - I3C NMR (50.32 MHz, CDC13):

Liebigs AnnJRecueill997, 21 13-2118

I-Azacyclododeca-3,8-diynes and 1,6-Diazacyclododeca-3,8-diynes FULL PAPER 6 = 82.2, 46.6, 39.9. - HRMS; (CI0Hl4N2): calcd. 162.1156; found 162.1136. - CI0Hl4NZ (162.1): calcd. C 74.04, H 8.70, N 17.27; found C 74.19, H 8.77, N 17.41. - 18b: Viscous, slightly yellow oil. - 'H NMR (200 MHz, CDC13): 6 = 3.51 (s, 12 H), 2.36 (s , 9 H). - 13C NMR (50.32 MHz, CDC13): 6 = 80.6, 45.2, 41.3. - MS (EI); mlz (%I): 243 (OS), 242 (l.O), 211 (8), 199 (15). - CI5Hz1N3 (243): calcd. C 74.04, H 8.70, N 17.27; found 73.80, H 8.74, N 17.18. - 19b: Viscous, slightly yellow oil. - IH NMR (200 MHz,

MHz, CDC13): 6 = 80.3, 44.9 41.3. - HRMS; C20H2sN4: calcd. 324.2314; found 324.2257. - C20H28N4 (324.2): calcd. C 74.04, H 8.70, N 17.27; found C 73.80, H 8.68, N 17.11.

CDC13): 6 = 3.43 ( s , 16 H), 2.46 (s, 12 H). - 13C NMR (50.32

NN'-Diethyl-l,6-diazacyclodeca-3,8-diyne (2c), NN,N'-Trie- thyl-1,6,Il-triazacyclopentadeca-3,8,I3-triyne (18c), and N,N',W, N"'- Tetraethyl-1,6, I I, I6-tetraazacycloeicosa-3,8,13, IS-tetrayne (19c): Starting materials: 22.5 g (0.2 mol) of an aqueous (40%) solution of ethylamine in 500 ml of THF, 42.4 g (0.2 mol) of 1,4- dibromo-2-butyne (15) in 500 ml of THF, 69 g (0.5 mol) of K2C03, 2.5 1 of THF and 9 ml of water. Column chromatography on A1203 111 (cyclohexanelethyl acetate 10: 1) yielded 1.6- 1.85 g (8- 10%) of 2c, 1.0-1.5 g (5-7%) of 18c and 0.59-0.88 g (4-6%) of 19c. - 2c: Colorless crystals, m. p. 58°C from ether. - 'H NMR (200 MHz, CDC13): 6 = 3.55 (s, 8 H), 2.85 (q, 4 H), 1.09 (t, 9 H). I3C NMR (50.32 MHz, CDC13): 6 = 82.8, 45.0, 43.1, 13.0. - MS (CI; CH4, 40°C); mlz: 327 [M+ + 421, 316 [M+ + 311,315 [M+ + 301, 287 [M+ + 21, 286 [M+ + I], 285 [M+], 284 [M+ - I]. - HRMS (EI); CI2Hl8N2: calcd. 190.1470, found 190.1465. - 18c: 'H NMR (200 MHz, CDC13): 6 = 3.55 (s, 12 H), 2.61 (q, 6 H), 1.07 (1, 9 H). - I3C NMR (50.32 MHz, CDC13): 6 = 80.5, 45.0, 43.1, 13.0. - IR (CDCI3): P = 2166 cm-', 2930, 2868, 2816, 2236, 2194, 1456, 1431, 1422. - MS (CI; CH4, 40°C); mlz: 327 [M+ + 421, 316 [M+ + 311, 315 [M+ + 301, 287 [M+ + 21, 286 [M+ + I], 286 [M+ + I], 285 [M+], 284 [M+ - I]. - 19c: Colorless, viscous oil. - 'H NMR (200 MHz, CDCl,): 6 = 3.38 (s, 16 H), 2.58 (q, 8

46.8, 42.3, 12.8. - MS (CI; CH4, 90°C); mlz: 421 [M+ + 411, 410 [M+ + 301, 409 [M+ + 291, 382 [M+ + 21, 381 [M+ + 11, 380

H), 106 (t, 12 H). - 13C NMR (50.32 MHz, CDC13): 6 = 79.8,

[M+], 379 [M+ - 11.

N -Diisopropyl-I ,6-diuzacyclodeca-3,8-diyne (2d), N N', N 1 - Triisopropyl-I,6, I 1 -triazacyclopentadeca-3,8,13-triyne (18d) and N, N',N",N"'- Tetraisopropyl-I,6,I 1,16-tetraazaeicosa-3,8,13,18- tetrayne (19d): Starting materials: 11.8 g (0.2 mol) of isopropylamine in 500 ml of THF, 42.4 (0.2 mol) of 1,4 dibromo-2-butyne (15) in 500 ml of THF, 69 g (0.5 mol) of K2C03, 1.5 1 of THF and 9 ml of water. Column chromatography on Al2O3 I11 (cyclohexanel ethyl acetate 1O:l) yielded 1.96-3.27 g (9-15%) of 2d, 1.09-1.74 g (5-8%) of 18d and 0.87-1.31 g (4-6%) of 19d. - 2d: Colorless crystals, m. p. 126°C. - 'H NMR: 6 = 3.60 (s, 8 H), 3.32 (sept, 2 H), 1.11 (d, 12 H). - I3C NMR: 6 = 82.7, 47.3, 43.3, 21.3. - HRMS; CIOH14N2: calcd. 218.1783; found 218.1796. - C10H14N2 (218.2): calcd. C 77.01, H 10.16, N 12.83; found C 76.78, H 10.13, N 12.76. - 18d: Colorless crystals, m. p. 52-55°C. - 'H NMR: 6 = 3.61 (s, 12 H), 2.99 (sept, 3 H), 1.09 (d, 18 H). - I3C NMR: 6 = 80.9, 50.8, 41.4, 20.3. - HRMS; C21H33N3: calcd. 327.2675; found 327.2616. - C21H33N3 (327.3): calcd. C 77.01, H 10.16, 12.83; found C 76.85, H 10.17, N 12.75. - 19d: Colorless crystals, m. p. 45-48°C. - 'H NMR: 6 = 3.57 (s, 16 H), 3.02 (sept, 4 H),

C28H44N4: calcd. 436.3566, found 436.3561. - C28H44N4 (436.4): calcd. C 77.01, H 10.16, N 12.83; found C76.92, H 10.06, N 12.81.

~N-Di-tert-butyl-l,6-diazacyclodeca-3,S-diyne (2e): Starting materials: 14.6 g (0.2 mol) of tert-butylamine in 500 ml of THF,

1.08 (d, 24 H). - NMR: 6 = 80.6, 51.0, 43.3, 20.5. - HRMS;

42.4 g (0.2 mol) of 1,4-dibromo-2-butyne (15) in 500 ml THF, and 9 ml of water. Column chromatography on A1203 111 (cyclohexane/ ethyl acetate 1O:l) yielded 2.21 g (9%) of 2e as colorless crystals (from ether), m. p. 45°C. - 'H NMR (200 MHz, CDC13): 6 = 3.46

85.8, 40.4, 55.2, 27.9. - MS (EI); mlz (%): 246 (6), 231 (38), 175 (22), 161 (13), 134 (12), 133 (17), 132 (ll), 119 (16), 118 (38), 117 (14), 108 (29), 105 (28), 91 (32), 65 (21), 57 (64), 41 (100). - HRMS; CI6Hz6H2: calcd. 246.2096; found 246.2125.

( s , 8 H), 1.15 ( s , 18 H). - I3C NMR (50.32 MHz, CDC13) 6 =

N N -Dicyclohexyl-1,6-diazacyclodeca-3,8-diyne (20: Starting materials: 198.8 mg (0.2 mol) of cyclohexylamine in 500 ml of THF, 42.4 g (0.2 mol) of 1,4-dibromo-2-butyne (15) in 500 ml of THF, 69 g (0.3 mol) of K2C03, 2.5 1 of THF, and 9 ml of water. Column chromatography on A1203 111 (cyclohexanelethyl acetate 10: 1) yielded 2.98 g (10%) of 2f as colorless crystals, m. p. > 175°C (dec.) - 'H NMR: 6 = 3.61 (s, 8 H), 3.07 (m, 2 H), 2.08-1.02 (m, 20

mlz (%): 299 (2), 298 (lo), 297 (12), 255 (lo), 215 (14), 202 (18), 201 (23), 200 (55), 188 (13), 187 (40), 186 (12), 173 (17), 133 (20),

C20H30N2: calcd. 298.2409; found 298.2399.

H). - I3C NMR: 6 = 83.1, 54.9, 42.6, 30.8, 26.0, 25.3. - MS (EI);

132 (26), 120 (18), 118, 33), 105 (70), 93 (37), 41 (100). - HRMS;

N, N -Diphenyl-l,6-diazucyclodeca-3,8-diyne (2g) and N, N , N" - Triphenyl-I,6, I I-triazucyclopentadeca-3,8,13-triyne (18g): Starting materials: 18.6 g (0.2 mol) of aniline in 500 ml of THF, 78.8 g (0.2 mol) of 1,4-di-p-tosyl-2-butyne (16) in 500 ml of toluene yielded 1.43 g (5%) of 2g and 3.01g (7%) of 18g. - 2g: Colorless crystals, m. p. > 170°C (dec.) - 'H NMR: 6 = 7.23-6.67 (m, 10 H), 4.05

116.2, 82.7, 42.5. - HRMS (EI); C20H18N2: calcd. 286.1470; found 286.1471. - C20H18N2: calcd. C 83.88, H 6.34, N 9.78; found C

7.28-6.82 (m, 10 H), 4.01 (s, 8 H). - I3C NMR (75.46 MHz, CDCI3): 6 = 147.5, 129.0, 119.0, 115.5, 80.1, 40.8. - UVlVis

mlz: 462 [M+ + 331,460 [M+ + 311, 430 [M' + 11, 429 [M+], 428

( s , 8 H). - I3C NMR (75.46 MHz, CDC13): 6 = 147.1, 129.1, 119.4,

83.73, H 6.34, N 9.74. - 18g: 'H NMR (300 MHz, CDC13): 6 =

(CHC13): h (lg E) = 250 (4.53), 290 (3.70). - MS (CI; CH4, 240°C);

[M + - I], 380, 367, 337, 336.

N, N - Di-p-tolyl-l,6-diazacyclo3,8-diyne (2h) and N, N , N"- Tri-p- tolyl-1,6,Il-triazacyclopentadeca-3,8,I3-triyne (18h): Starting materials: 21.4 g (0.2 mol) of toluidine in 500 ml of THF, 78.8 g (0.2 mol) of 1,4-di-p-tosyl-2-butyne (16) in 500 ml of THF, 69 g (0.5 mol) of activated K2C03, and 2.5 1 of THE Column chromatography on silicagel (toluene/cyclohexane 1:l) yielded 1.57 g (5%) of 2h and 3.3 g (7%) of 18h. - 2h: Colorless crystals, m. p. 170°C (dec.) - 'H NMR: 6 = 7.01-6.81 (AA'BB', 8 H), 4.02 (s, 8 H), 2.31 (s , 6 H). - I3C NMR: 6 = 144.9, 129.5, 128.6, 116.4, 82.8, 42.7, 20.4. - MS (EI); mlz ("4): 316 [M+ + 21 (OS), 315 [M+ + 11 (3.4), 314 [M+] (12.3), 312 (0.Q 196 (21), 182 (25), 118 (34), 91 (loo), 77 (21), 65 (60), 51 (20). - C22H22N2 (314.18): calcd. C 84.04 H 7.05, N 8.91; found C 83.78, H 7.10, N 8.87. - 18h: Colorless crystals, m. p. > 170°C (dec.) - 'H NMR: 6 = 7.08-6.74

145.4, 129.5, 128.3, 115.7, 80.2, 41.1, 20.4. (AA'BB', 12 H), 3.99 (s , 12 H), 2.30 (s , 9 H). - I3C NMR: 6 =

I,6-Diazacyclodeca-3,8-diyne (2a): The experiments were carried out under argon in dried glassware. To carefully dried 1,2-dichloroethane 8.72 g (40 mmol) of 2d was added and refluxed for 2 h. After cooling to ambient temperature, 12.48 g (88 mmol) of 1-chloroethyl chloroformate (20) was added with a syringe under argon and heated under reflux until no 2d could be detected. After the reaction was terminated, the solvents were removed at 30-40°C under argon in vacuo. To the brown residue was added 250 ml of dry methanol and stirred overnight followed by heating it for 1.5 h under reflux. After removal of the solvent, 800 ml of water and 200

Liebigs Ann.lRecueill997, 2113-21 18 2117


ml of chloroform were added to the residue. To this mixture a solution of 2 M NaOH was added until pH > 11. The NaC1-saturated solution was extracted with chloroform. The organic phases were dried (K2C03) and concentrated until 50 ml were left. Subsequent column chromatography on silica gel (CHC13/methanol 10: 1) yielded 1.32-1.69 g (25-32'%) of 2a as a colorless hygroscopic powder which proved to be air-sensitive, m. p. 120°C. - 'H NMR:

HRMS; C8HI9N2: calcd. 134.0706; found 134.0775. - C8HI9N2 (134.1): calcd. C 71.61, H 7.51, N 20.88; found C 71.61, H 7.59, N 20.83.

6 = 3.46 (s, 8 H), 1.43 (2 H). - I3C NMR: 6 = 85.6, 39.8. -

Azacyclodeca-3,8-diyne (4a): The same procedure as for the preparation of 2a was used. Starting materials: 2.273 g (13 mmol) of 4d, 1.96 g (13.3 mmol) of 20, 120 ml of dry 1,2-dichloroethane and 60 ml of dry methanol. Column chromatography on silica gel (ethyl acetate) yielded 576 mg (33%) of 4a as white crystals, m. p. 92°C.

2.39-2.31 (m, 4H), 1.81-1.69 (m, 2 H), 1.47 (br., 1 H). - I3C

MS; mlz (YO): 134 (l), 133 (15), 132 (loo), 131 (12), 130 (19), 117 (33), 91 (26), 77 (26), 65 (19), 51 (24). - C9H11N (133.09): calcd. C 81.16, H 8.32, N 10.52; found C 81.09, H 8.30, N 10.51.

~ 'H NMR (200 MHz, CDC13): 6 = 3.49 (t, 4 H, 5J = 2.3 Hz),

NMR (50.32 MHz, CDC13): 6 = 86.7, 82.1, 39.7, 25.2, 19.9. - GC/

[ I ] H. Meier, Synthesis 1972, 235; V. Jager in Methoden Org. Chem. (Houhen- Weyl) 4th ed. 1977, vol. 5/2a, p. 33; A. Krebs, J. Wilke, Top. Curr. Chem. 1983, 109, 189; H. Meier, in Advances in Strain in Organic Chemistry (Ed.: B. Halton), JAI Press, 1991, 215; R. Gleiter, Angew Chem. 1992, 104, 29; Angew Chem. Int Ed. Engl.

1992, 31, 27; R. Gleiter, R. Merger in Modern Acetylene Chem- istry (Ed.: P. J. Stang, F. Diederich), VCH, Weinheim, 1995.

[*I E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Or- ganic Compounds, J. Wiley & Sons, New York 1994.

131 Reviews: J. B. Lambert, S. I. Featherman, Chem. Rev. 1975, 75, 61 1; I. D. Blackburne, A. R. Katritzky, Y Takeuchi, Acc. Chem. Res. 1975, 8, 300; M. Rubiralta, E. Girault, A. Diez, Piperidine, Elsevier, Amsterdam, 1991; J. J. Delpuech, in Cyclic Orga- nonitrogen Stereodynamics, (Ed.: J. B. Lambert, Y Takeuchi), Verlag Chemie, Weinheim, 1992, chapter 7.

L41 J. Ritter, R. Gleiter, H. Irngartinger, T. Oeser, J Am. Chem. Soc., submitted for publication.

L51 R. Gleiter, J. Ritter, Angew. Chem. 1994, 106, 2550; Angew. Chem. Int. Ed. Engl. 1994, 33, 2470.

[6] R. Gleiter, J. Ritter, Tetrahedron 1996, 52, 10383. 171 R. Gleiter, K. Hovermann, J. Ritter, B. Nuber, Angeiv. Chem.

1995, 107, 867; Angew. Chem. Int. Ed. Engl. 1995, 34, 789. [*I W. N. Smith, 0. F. Beumel, Jr., Synthesis 1974, 441. 1'1 P. Lennon, M. Rosenblum, J Am. Chem. Soc. 1983,105, 1233.

['"I P. J. M. Reijnders, H. R. Fransen, H. M. Buck, Red. Trav. Chim. Pays-Bas 1979, 98, 511.

[ I 1 ] G. F. Woods, D. N. Kramer, J Am. Chenz. Soc. 1947, 69, 2246; G. Baumeyer, G. Dittus, E. Miiller, in Methoden 0rg.Chem. (Houhen- Weyl) 4th ed. 1966, vol6, p. 335.

[ I 2 ] R. Gleiter, S. Rittinger, H. Langer, Chem. Ber. 1991, 124, 357. [ I3 ] R. Epsztein, N. Le Goff, Tetrahedron Lett. 1985, 26, 3203. [I4] T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley,

New York, 1981. [I5] R. A Olofson, J. T. Martz, J.-P. Senet, M. Piteau, T. Malfroot,

J Org. Chem. 1984, 49, 281; R. A. Olofson, D. E. Abbott, J: Org. Chem. 1984,49, 2795.

[I6] J. Gadamer, F. Knoch Arch.Pharm. 1921, 259, 135. [I7 ] Ev. Bruchhausen, J. Knabe, Arch. Pharm. 1954, 287, 601. [I8 ] J. Ritter, R. Gleiter, H. Irngartinger. T. Oeser, to be published.

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preparation of 1-azacyclododeca-3,8-diynes and 1,6-diazacyclododeca-3,8-diynes

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